Enhanced respiratory syncytial virus disease or protection from infection depends on the subtype used for adenoviral vector vaccination

人呼吸道合胞病毒（RSV）是五岁以下儿童严重呼吸道感染的最常见原因。目前，没有获得许可的预防性疫苗存在，这至少部分也是由于以前的疫苗试验失败造成的。在20世纪60年代，与安慰剂疫苗接种的儿童相比，用福尔马林灭活疫苗免疫的儿童在获得天然RSV感染后发展为增强的呼吸道疾病（ERD），甚至导致疫苗组中的两人死亡。几项研究描述了疫苗诱导ERD的可能原因。由于这些原因可能因疫苗接种方法而异，因此需要仔细评估每种新疫苗候选物是否存在ERD。最近，我们报道了一种非常有效的免疫方案，在小鼠和恒河猴的基础上的DNA引物/腺病毒载体加强战略与腺病毒血清型Ad 5。由于Ad 5的高血清阳性率和大型HIV疫苗试验（STEP研究）的阴性结果，罕见的人血清型或猴源性腺病毒成为疫苗研究的焦点。在我们的研究中，一种基于血清型Ad 19 a的新型腺病毒载体在小鼠中RSV感染后导致ERD。这是非常出乎意料的，因为使用基于Ad 5的载体的相同方案有效地保护小鼠免受RSV感染。这表明，载体系统中的微小差异可能会对免疫后果产生巨大影响。在拟议的研究中，将系统地分析潜在的机制。虽然两种载体都诱导了对RSV-F的体液和细胞免疫应答，但局部粘膜免疫的质量似乎不同。在研究的第一部分，将根据载体系统和应用途径详细分析疾病进展的不同过程。这包括病毒复制的动力学研究、局部细胞因子/趋化因子环境、细胞浸润以及感染肺组织的组织学分析。其次，与保护或ERD相关的免疫学参数将通过适当的耗竭或转移实验来揭示。最后，将评估载体内在特性对这些差异疫苗诱导的免疫应答的影响。具体而言，两个载体的载体向性的作用将得到阐明。特别是，Ad 19 a对抗原呈递细胞的转导和激活很少被描述，但可能对所产生的免疫性有巨大的影响。了解如此密切相关的载体系统的使用如何导致如此相反的结果将是疫苗学领域的极大兴趣。

The human respiratory syncytial virus (RSV) is the most common cause of severe respiratory tract infection of children under the age of five years. Currently, no licensed, prophylactic vaccine exists, which is at least partially also caused by the failure of former vaccine trials. In the 1960s, children immunized with a formalin-inactivated vaccine developed an enhanced respiratory disease (ERD) after acquiring natural RSV infection compared to placebo vaccinated children, even resulting in two deaths in the vaccine group. Several studies described possible causes for the vaccine-induced ERD. Since these causes could vary depending on the vaccination approach, every new vaccine candidate needs to be evaluated carefully in regard to possible ERD. Recently, we reported on a very efficient immunization protocol in mice and rhesus macaques based on DNA prime/adenoviral vector boost strategy with an adenovirus serotype Ad5. Due to the high seroprevalence of Ad5 and negative results from a large HIV vaccine trial (STEP study), rare human serotypes or monkey-derived adenoviruses reached into the focus of vaccine research. In our studies, a new adenoviral vector based on serotype Ad19a results in ERD after an RSV-infection in mice. This was highly unexpected since the same protocol with Ad5-based vectors efficiently protected mice from RSV infection. This demonstrates that minimal differences in the vector systems could hugely impact on the immunological consequences. In the proposed study, the underlying mechanism will be systematically analyzed. Although both vectors induced humoral and cellular immune response to RSV-F, the quality of the local, mucosal immunity seemed to be different. In the first part of the study, the different courses of disease progression will be analyzed in detail depending on the vector system and the application route. This includes kinetic studies of viral replication, local cytokine/chemokine milieu, cellular infiltrates as well as histological analyses of the infected lung tissue. Secondly, the immunological parameters correlated either with protection or ERD will be revealed by appropriate depletion or transfer experiments. Finally, the impact of vector-intrinsic properties on these differential vaccine-induced immune responses will be evaluated. Specifically, the role of the vector tropism of the two vectors will be elucidated. Particularly, the transduction and activation of antigen-presenting cells by Ad19a are rarely described, but might have huge implications for the resulting immunity.To understand how the use of so closely related vector systems can result in such contrary outcomes will be of great interest for the field of vaccinology.